DESCRIPTION: (Applicant's Abstract) This research will investigate biological correlates of behavioral indices related to drug abuse vulnerability. Drug abuse is a complex interaction among cultural, social, and psychological risk factors, but biological factors also play a role. Research on risk factors includes experimental strategies that examine associations betweem biological and behavioral indices of dependence in humans. Previous PET studies have suggested that decreased glucose metabolism in the frontal cortex and limbic system are associated with drug-induced euphoria. Drug reinforcement studies have shown that there are large differences in subjective responses to amphetamine and the propensity to choose to reexperience its effects. Approximately half of tested normals show a positive mood enhancement to amphetamine and choose to self-administer it over placebo. The other half show negative mood increases and choose to self-administer placebo over amphetamine. The first study proposes to determine whether amphetamine produces differential effects on brain glucose metabolism, either in magnitude or regions affected. We predict that specific regions of the brain will show decreases in metabolic rate following the administration of amphetamine in those for whom amphetamine serves as positive reinforcer whereas a different pattern of metabolic changes will be observed in those who find its effects aversive. The second study is designed to extend findings from preclinical studies in rats showing that high levels of reactivity predict individual differences in the effects of amphetamine related to vulnerability. This study will examine the relationships among responses to a novel environment (reactivity), the actions of amphetamine on activity levels, reactions to auditory stimuli, neurotransmitter and neurohormonal levels, and whether these different responses in turn predict individual differences in the subjective and reinforcing effects of amphetamine. A knowledge of biological differences related to vulnerability can be useful for prevention efforts, by allowing a means of recognizing high risk individuals, and treatment, by providing a rationale for medication development.